# Age-related Mechanisms Underlying Cognitive Resilience in Response to Amyloid Beta

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $362,500

## Abstract

ABSTRACT
 A universal characteristic of aging animals is the dramatic decrease in their ability to respond to stress and
maintain homeostasis, i.e. resilience. This is believed to be a key factor in the dramatic increase in age-related
diseases and deaths observed in the elderly. This request for supplemental funding to our resilience grant entitled
“Short-term measurements of physical resilience as a predictor of healthspan in mice” is designed to study the
effect of age on the resilience of the brain to AD. Unfortunately, there are no studies with mice that have critically
evaluated cognitive resilience in old mice comparable to the ages when AD develops in humans. Thus, the
vulnerability of the brain of older mice to AD remains unexplored. We will test the following hypothesis:
Decreased resilience of the aging brain results in increased susceptibility to Aβ1-42-induced cognitive
decline and manipulations, such as rapamycin, that increase longevity and delay aging will improve the
resilience of the brain to Aβ-induced cognitive decline. The effect of age on the resilience of the brain to Aβ
will be tested by injecting Aβ1-42 directly into the brains of young and old mice. This is supported by our preliminary
data demonstrating that old (24 months) male mice are more susceptible to amyloid beta (Aβ1-42)-induced
cognitive deficits compared to young (6 months) mice. The following aims are proposed: Specific Aim 1:
Determine whether aged mice show increased susceptibility to Aβ-induced cognitive deficits. Aβ1-42 (or
peptide control) will be injected into the hippocampus of young (5-7 m), middle (15-18 m) and old (24-26 m) male
and female mice. Two weeks post-injection, we will perform a battery of behavioral tests to assess cognitive
resilience followed by comprehensive multi-parametric magnetic resonance imaging (MRI) to measure
alterations in blood-brain barrier (BBB) permeability, neuroinflammation and metabolism in the brain. Specific
Aim 2: Determine if rapamycin can improve the resilience of the brain to Aβ1-42. Studies show that
rapamycin increases lifespan in mice and reduces various age-related pathologies. We will feed rapamycin (14
and 42ppm) starting at 18 months of age, and Aβ1-42 will be injected into the hippocampus at 24 months of age.
Cognitive resilience will be assessed using the endpoints described in Aim 1. Rigorous analysis of these data
will answer the critical question of whether pathways mediating lifespan extension increase cognitive resilience
and decrease susceptibility to Aβ1-42. These experiments are critical to determine the translational potential of
lifespan extending interventions in alleviating the incidence and/or progression of AD.

## Key facts

- **NIH application ID:** 10123518
- **Project number:** 3R01AG057424-04S1
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** ARLAN G. RICHARDSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,500
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123518

## Citation

> US National Institutes of Health, RePORTER application 10123518, Age-related Mechanisms Underlying Cognitive Resilience in Response to Amyloid Beta (3R01AG057424-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123518. Licensed CC0.

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